Previous studies by ourselves and others have demonstrated that immunoregulatory-suppressor lymphocytes are both a component of the normal immune system and are associated with the pathogenesis of several immunodeficiency diseases. Suppressor cells appear to function through the release of soluble immunoregulatory factors. Natural killer (NK) cells and cells mediating antibody-dependent cellular cytotoxicity (ADCC) may also have immunoregulatory activities in addition to their role in immune surveillance against tumors. These investigations extend our ongoing analysis of the cellular and biochemical mechanisms underlying suppressor-cell activity and examine the complex interactions regulating NK and ADCC functions. Our studies indicate that these cytotoxic activities may be self-regulated through an autologous-mixed lymphocyte reaction (AMLR). We have recently isolated and partially characterized a soluble suppressor factor (SSF), apparently derived from the AMLR, which inhibits a wide spectrum of humoral and cell-mediated immune functions, including NK and ADCC activities. SSF is a 17 kilodalton polypeptide with lectin-like activity potentially specific for monosaccharides on the surface of regulated lymphocytes. The inhibitory activity of SSF can be reversed in vitro with interferon and interleukin-2. We have observed that low levels of similar soluble suppressor activity can also be found in sera from healthy donors and in significantly increased levels in sera from patients with malignant disease. Serum SSF activity will thus be correlated with extent of disease and any associated deficiencies of immunologic function. Purified culture-derived and serum-derived SSF is presently being characterized and compared biochemically. We shall prepare heterologous and monoclonal antibodies against SSF for use in quantitative immunoassays. Exogenous modulation of immunoregulatory activity may have subsequent therapeutic potential. Thus, we further intend to examine the ability of irradiation, immunopharmacologically active compounds, and biological modifier substances to stimulate or decrease suppressor-cell activity in vitro with the eventual goal of therapeutic application to immunodeficiency states and autoimmune disorders. Clinical studies will examine serum-\and culture-derived SSF in aging and immunodeficiency diseases. Murine and human SSF will be used in vivo to treat the disorder of NZB/W F[unreadable]1[unreadable] mice associated with suppressor-cell deficiency. (IS)